Regulation of DC Activity by Memory and Effector CD8+ T Cells

Summary

Principal Investigator: Pawel Kalinski
Abstract: In the previous (first) period of funding of this project we demonstrated that memory and effector CD8+ T cells exert reciprocal, DC-killing ("suppressive") versus DC-activating ("helper") activities and differentially affect the immunologic and anti-tumor activity of cancer vaccines. Our data demonstrate that effector CD8+ T cells kill antigen (Ag)-bearing DCs in a perforin (Pfn)- and Granzyme B (GrB)-dependent mechanism. In contrast, memory CD8+ T cells play a "helper" role, inducing the DC expression of the serpin PI9 (CAP3/B9/SPI6), an endogenous GrB inhibitor, and protecting DCs from cytotoxic T cell (CTL)-mediated killing. They also induce type-1 polarization of DCs, manifested by their enhanced production of IL-12p70, enhanced ability to support Th1- and CTL responses and to mediate antitumor effects. Moreover, we have demonstrated that the nominally "suppressive" effector CTLs can be converted to "helper cells" following pharmacologic blockade of their cytolytic machinery, or following their TCR-independent activation with IFN plus IL-18. Based on these data, we hypothesize that the elimination of tumor-associated antigenous GrB inhibitor, and protecting DCs from cytotoxic T cell (CTL)-mediated killing. They also induce type-1 polarization of DCs, manifested by their enhanced production of IL-12p70, enhanced ae propose to test the above hypotheses and to develop means to counteract the suppressive impact of pre-existing tumor-specific CD8+ T cells and to utilize their "helper" potential in the following Specific Aims: 1. Identify the molecular mechanisms of DC-killing and DC protection/polarization by human CD8+ effector (Teff) versus memory (Tmem) cells, as potential targets of immunointervention. 2. Validate the key mechanisms of DC modulation by mouse CD8+ Teff and Tmem cells in vitro. Success of tehse studies will allow us to optimally design prospective in vivo mouse studies testing the relative contribution of the individual regulatory mechanisms to the Teff -and Tmem-mediated immune regulation in vivo and to develop strategies to counteract the CTL-mediated DC killing elimination and to utilize the CD8+ T cell-dependent help in mouse models of therapeutic cancer vaccination. The positive outcome of this project and it follow-up studies, will help us to understand basic principles of immune memory and regulatory functions of Teff and Tmem cells, and will allow us to develop new off-the-shelf therapeutic cancer vaccines and combined cancer therapies utilizing the principles of protection and polarization of endogenous DCs of cancer patients, in order to achieve continued immunologic and therapeutic effects of vaccination against established cancer.
Funding Period: ----------------2002 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Helper function of memory CD8+ T cells: heterologous CD8+ T cells support the induction of therapeutic cancer immunity
    Yutaro Nakamura
    Department of Surgery, University of Pittsburgh, Eye and Ear Institute, PA 15213 1863, USA
    Cancer Res 67:10012-8. 2007
  2. pmc NF-κB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells
    Ravikumar Muthuswamy
    Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
    Cancer Res 72:3735-43. 2012
  3. pmc Immunotherapy of cancer in 2012
    John M Kirkwood
    Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA
    CA Cancer J Clin 62:309-35. 2012
  4. pmc Lymphocyte-polarized dendritic cells are highly effective in inducing tumor-specific CTLs
    Erik Berk
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Vaccine 30:6216-24. 2012
  5. pmc Ability of mature dendritic cells to interact with regulatory T cells is imprinted during maturation
    Ravikumar Muthuswamy
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
    Cancer Res 68:5972-8. 2008
  6. pmc Type 1-polarized dendritic cells loaded with autologous tumor are a potent immunogen against chronic lymphocytic leukemia
    Je Jung Lee
    Department of Surgery and Medicine, University of Pittsburgh, University of Pittsburgh Cancer Institute, 1 46 Hillman Cancer Ctr, 5117 Centre Ave, Pittsburgh, PA 15213, USA
    J Leukoc Biol 84:319-25. 2008
  7. pmc Memory CD8+ T cells protect dendritic cells from CTL killing
    Payal B Watchmaker
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 1863, USA
    J Immunol 180:3857-65. 2008
  8. ncbi Helper roles of NK and CD8+ T cells in the induction of tumor immunity. Polarized dendritic cells as cancer vaccines
    Pawel Kalinski
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 1863, USA
    Immunol Res 36:137-46. 2006
  9. pmc Type-1 polarized dendritic cells primed for high IL-12 production show enhanced activity as cancer vaccines
    Adam S Giermasz
    Department of Surgery, Hillman Cancer Center, University of Pittsburgh, UPCI Research Pavilion, Room 1 46b, 5117 Center Avenue, Pittsburgh, PA 15213 1863, USA
    Cancer Immunol Immunother 58:1329-36. 2009
  10. pmc Effective immunotherapy against murine gliomas using type 1 polarizing dendritic cells--significant roles of CXCL10
    Mitsugu Fujita
    Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
    Cancer Res 69:1587-95. 2009

Scientific Experts

  • Pawel Kalinski
  • Ravikumar Muthuswamy
  • Erik Berk
  • Robbie B Mailliard
  • John M Kirkwood
  • Payal B Watchmaker
  • Yutaro Nakamura
  • Julie A Urban
  • William Gooding
  • Je Jung Lee
  • Jeffrey L Wong
  • Eva Wieckowski
  • Todd A Reinhart
  • Mitsugu Fujita
  • Adam S Giermasz
  • Simon C Watkins
  • Payal Watchmaker
  • Hideho Okada
  • Kotaro Sasaki
  • Julie Urban
  • Amer H Zureikat
  • Soldano Ferrone
  • Lisa H Butterfield
  • David L Bartlett
  • Daniel Normolle
  • Beth Fallert Junecko
  • Ahmad A Tarhini
  • The Minh Luong
  • Hassane Zarour
  • Herbert J Zeh
  • Gurkamal S Chatta
  • Michael T Lotze
  • Karolina Palucka
  • Stergios J Moschos
  • Jacques Banchereau
  • Robbie M Mailliard
  • Howard Edington
  • Rachel L Cumberland
  • Gregory A Gibson
  • Ryo Ueda
  • Gary Kohanbash
  • Edward R Kastenhuber
  • Xinmei Zhu
  • Heather A McDonald
  • S Marieke Van Ham
  • David Bartlett
  • Kenneth A Foon
  • Louis D Falo
  • Fumihiko Nishimura
  • Brian Sheridan
  • Walter J Storkus
  • Adam Giermasz
  • Rachel Cumberland
  • Robert L Hendricks
  • Adriana T Larregina

Detail Information

Publications18

  1. pmc Helper function of memory CD8+ T cells: heterologous CD8+ T cells support the induction of therapeutic cancer immunity
    Yutaro Nakamura
    Department of Surgery, University of Pittsburgh, Eye and Ear Institute, PA 15213 1863, USA
    Cancer Res 67:10012-8. 2007
    ....
  2. pmc NF-κB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells
    Ravikumar Muthuswamy
    Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
    Cancer Res 72:3735-43. 2012
    ..Together, our findings suggest the feasibility of exploiting NF-κB hyperactivation in the tumor microenvironment to selectively enhance T(eff) entry into colon tumors...
  3. pmc Immunotherapy of cancer in 2012
    John M Kirkwood
    Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA
    CA Cancer J Clin 62:309-35. 2012
    ....
  4. pmc Lymphocyte-polarized dendritic cells are highly effective in inducing tumor-specific CTLs
    Erik Berk
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Vaccine 30:6216-24. 2012
    ..These results demonstrate the feasibility of generation of polarized DC1s using autologous lymphocytes...
  5. pmc Ability of mature dendritic cells to interact with regulatory T cells is imprinted during maturation
    Ravikumar Muthuswamy
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
    Cancer Res 68:5972-8. 2008
    ....
  6. pmc Type 1-polarized dendritic cells loaded with autologous tumor are a potent immunogen against chronic lymphocytic leukemia
    Je Jung Lee
    Department of Surgery and Medicine, University of Pittsburgh, University of Pittsburgh Cancer Institute, 1 46 Hillman Cancer Ctr, 5117 Centre Ave, Pittsburgh, PA 15213, USA
    J Leukoc Biol 84:319-25. 2008
    ..4-38 times) of functional CD8+ T cells against CLL cells. The current demonstration that autologous tumor-loaded alphaDC1 are potent inducers of CLL-specific T cells helps to develop improved immunotherapies of CLL...
  7. pmc Memory CD8+ T cells protect dendritic cells from CTL killing
    Payal B Watchmaker
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 1863, USA
    J Immunol 180:3857-65. 2008
    ....
  8. ncbi Helper roles of NK and CD8+ T cells in the induction of tumor immunity. Polarized dendritic cells as cancer vaccines
    Pawel Kalinski
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 1863, USA
    Immunol Res 36:137-46. 2006
    ..The results of these studies allowed us and our colleagues to design phase I/II clinical trials incorporating the paradigms of DC polarization and helper activity of effector cells in cancer immunotherapy...
  9. pmc Type-1 polarized dendritic cells primed for high IL-12 production show enhanced activity as cancer vaccines
    Adam S Giermasz
    Department of Surgery, Hillman Cancer Center, University of Pittsburgh, UPCI Research Pavilion, Room 1 46b, 5117 Center Avenue, Pittsburgh, PA 15213 1863, USA
    Cancer Immunol Immunother 58:1329-36. 2009
    ..The current data help to explain the previously reported Th1-driving and anti-tumor activities of IL-4, and demonstrate that type-1 polarization increases in vivo activity of DC-based vaccines...
  10. pmc Effective immunotherapy against murine gliomas using type 1 polarizing dendritic cells--significant roles of CXCL10
    Mitsugu Fujita
    Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
    Cancer Res 69:1587-95. 2009
    ..Collectively, these findings show the anti-CNS glioma effects of DC1-based therapy and a novel role of CXCL10 in the immunologic and therapeutic activity of DC-based cancer vaccines...
  11. pmc Dendritic cell-based therapeutic cancer vaccines: what we have and what we need
    Pawel Kalinski
    Department of Surgery, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Res Pavilion, Suite 1 46, 5117 Center Avenue, PA 15213 1863, USA
    Future Oncol 5:379-90. 2009
    ..Furthermore, recent studies also identify the tools to counteract such phenomena, in order to assure the desirable induction of Th1-cytotoxic T lymphocytes, NK-mediated type-1 immunity and appropriate homing of effector cells to tumors...
  12. pmc Dendritic cells in immunotherapy of established cancer: Roles of signals 1, 2, 3 and 4
    Pawel Kalinski
    University of Pittsburgh, Department of Surgery, The University of Pittsburgh Cancer Institute, Hillman Cancer Center, Suite 1 46, Pittsburgh, PA 15213, USA
    Curr Opin Investig Drugs 10:526-35. 2009
    ....
  13. pmc Generation of stable Th1/CTL-, Th2-, and Th17-inducing human dendritic cells
    Pawel Kalinski
    Department of Surgery, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
    Methods Mol Biol 595:117-33. 2010
    ....
  14. pmc Independent regulation of chemokine responsiveness and cytolytic function versus CD8+ T cell expansion by dendritic cells
    Payal B Watchmaker
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
    J Immunol 184:591-7. 2010
    ....
  15. pmc Polarized dendritic cells as cancer vaccines: directing effector-type T cells to tumors
    Pawel Kalinski
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, United States
    Semin Immunol 22:173-82. 2010
    ..These developments allow for selective induction of tumor-specific T cells with desirable effector functions and tumor-relevant homing properties and to direct the desirable types of immune cells to tumors...
  16. pmc Type-1 polarized dendritic cells loaded with apoptotic prostate cancer cells are potent inducers of CD8(+) T cells against prostate cancer cells and defined prostate cancer-specific epitopes
    Eva Wieckowski
    Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Prostate 71:125-33. 2011
    ....
  17. pmc Helper activity of natural killer cells during the dendritic cell-mediated induction of melanoma-specific cytotoxic T cells
    Jeffrey L Wong
    Department of Surgery, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 1863, USA
    J Immunother 34:270-8. 2011
    ..These results indicate that the helper function of NK cells can be used in clinical settings to improve the effectiveness of DC-based cancer vaccines...
  18. pmc Dendritic cells in cancer immunotherapy: vaccines or autologous transplants?
    Pawel Kalinski
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 1863, USA
    Immunol Res 50:235-47. 2011
    ....